1. health and fitness
2. disease

Drug therapy in renal failure
Kari Laine, MD, PhD
University of Turku & medbase Ltd
Causes of renal failure
• Kidney diseases
• Infections (glomerulonephritis); pyelonephritis seldom
causes chronic renal failure
• Polycystic kidney diseases
• Drug- or chemical-induced injury
• Secondary renal injury caused by a primary disease
• DIABETES – type 2 diabetes a growing problem
• High blood pressure and ischemic nephropathy
• Age – disease (diabetes, hypertension, ischemia)
• Renal function decreases on average by 1% per year after
age 30 years
Prevalence of renal failure
• In the U.S. 35.000.000 people are estimated to
suffer from chronic renal failure
• 13% of the population
• Measured GFR<60 ml/min or demonstrated renal injury
• A recent meta-analysis estimated that in the
Western population 23%-36% of people >64years
of age has GFR<60 ml/min
Blix HS et al.
Nephrol Dial Transplant 2006;21:3164-71.
• Prospective study in general hospitals
• 201 patients (GFR<60 ml/min; 25% of the whole population) used an
average of 10 drugs
• Approximately 40% of drugs were harmful to the kidneys or required
modification of the dose; 5% fully contraindicated
• Almost all patients were co-administered a minimum of two harmful
drugs
• Typical risk drug toxicity in 62% of exposed patients
• 26% of risk drug exposures caused toxicity
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–
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Beta-lactam antibiotics, ciprofloxacin, aminoglycosides
antithrombotic agents and anticoagulants
anti-inflammatory drugs, codeine, tramadol
ACE-inhibitors/sartans, spironolactone/potassium
Allopurinol, metformin, sulphonylureas
Determination of renal function
• The exact glomerular filtration rate (GFR) can
only be determined by means of radioactive
markers exclusively eliminated by glomerular
filtration:
•
•
•
•
•
51Cr-EDTA, 99mTc-DTPA, 125I-iothalamate
Administration: i.v.
Tracer clearance is measured from 3-5 blood samples
Determination with a gamma counter
Used also for monitoring the safety of the use of
nephrotoxic drugs
MDRD
(Modification of Diet in Renal Disease)
•
k
uses a formula with four variables:
GFRMDRD = 186 x [serum crea]-1.154 x [age]-0.203
• For females, the coefficient is 0.742
• Accurate estimate with values less than 60 ml/min
• Weakness: when GFR >60 ml/min or in critically ill
J Am Soc Nephrol 16: 459-466, 2005
MDRD accuracy
J Am Soc Nephrol 16: 459-466, 2005
Cockcroft-Gault
1,23 x [140 – age (v)] x [weight (kg)]
GFRCG =
S/P-Creatinine (μmol/l)
• For females, the coefficient is 0.85
• In obese patients, ideal body weight must be used
• Gives an accurate estimate when renal function is
near normal (GFR >60 ml/min); if value calculated
with MDRD >60 ml/min,
prompts for
height and weight for calculating ideal body weight
and determines GFR using the Cockcroft-Gault
formula
Renal failure classification
Divided into four categories based on glomerular
filtration rate in accordance with the guidelines of the
European Medicines Agency (EMA) :
1. GFR 80-50 ml/min - mild
2. GFR 50-30 ml/min
3. GFR 30-10 ml/min
4. GFR <10 ml/min
renal failure
- moderate renal failure
- severe renal failure
- end-stage renal failure; dialysis
patient
Excretion of drugs in the nephron
(1.25 million / kidney)
Glomerulus filtration
- normally 125 ml/min; decreases by age
- e.g. NSAIDs decrease; circulation ↓
- protein binding reduces
Active transport into the tubulus
- anions OAT/OATP; beta-lactams
- cations OCT/OCTN; metformin
- P-gp and MRP2; digoxin
- Proximal tubulus
Passive reabsorption
- most drugs; pH and intratubular flow
rate have an influence
Active transport out of the tubulus
- proximal tubulus
- peptids PEPT1/2; glucose
Effects of renal injury on the
pharmacokinetics of drugs
• Glomerular injury (diabetes)
• Decreased glomerular filtration
• Tubular injury (drugs)
Renal clearance ↓
-significant whenever renal
clearance exceeds 30% of total
clearance
• Decreased active tubular excretion
• Decreased number of nephrons
– Decreased activation of vitamin D
• Active vitamin D derivatives must be used in end-stage
renal failure, e.g. alfacalcidol
– Decreased clearance of insulin and glucagon
Relevance of metabolites
• Prodrugs
– Parent drug inactive, pharmacologic effect from
metabolites; e.g. codeine
• Parent drug and metabolite both active
– E.g. risperidone, oxycodone
• Even glucuronide metabolites may be active
– E.g. midazolam, morphine
Metabolites often accumulate in renal failure – it is important
to be familiar with activity and kinetics and, if necessary, take
them into account in concentration measurements!!
Extra-renal effects
• Renal failure has an effect on
– Absorption of medicines
• E.g. iron absorption is reduced
– Distribution of drug ingredients
• Serum protein concentration and binding capacity of tissues are
reduced as a result of renal injury (albumin leaking into the urine
and accumulation of uremic components)
• Total concentration is reduced but free concentration may remain
unchanged or increase
– Drug metabolism and excretion into bile
• Effects in phase I (2B6, 2C9, 2C19) and phase II (NAT, UGT2B7)
• Hydrolysis of conjugates may occur in enterohepatic circulation;
excretion into bile may be saturated; reduced transport activity
(OATP, P-gp)??
• Renal failure may affect the pharmacokinetics of a drug,
even though renal clearance would not be of significant
importance to total clearance:
– Mechanism: uremic toxins and elevated cytokine activity,
which inhibit metabolic functions of the liver??
– E.g. bupropion
• Renal clearance <1% of total clearance
• Renal failure increases exposure to bupropion by 130%
The amount of the drug excreted in urine is not a fully
reliable basis to determine the pharmacokinetics of the drug in
renal failure
• Response may change; e.g. beta blockers
Dialysis treatment
• Dialysis treatment can be given as peritoneal
dialysis or hemodialysis
• Dialysis treatment is commenced latest when
GFR falls below 10% of normal (< 10 ml/min)
• Incidence figures:
– 1/3500 inhabitants in chronic dialysis treatment
– Annually, 94 new treatments are commenced per
million inhabitants
Hemodialysis treatment
• Intermittent, 3 times a week, 4–5 hours per session
• Circulation is connected to the dialysis machine
• Dialysis occurs through the thin walls of capillary walls of the
dialyser
• Uremic toxins and the superfluous fluid pass through this
membrane based on their concentration and size
Peritoneal dialysis treatment
• Executed via a peritoneal dialysis cannula; capillary walls of the
peritoneum serve as dialysis membranes
• 2–3 litres of hyperosmolar fluid (natrium, glucose and lactate/bicarbonate
buffer) is introduced into the peritoneal cavity
• The fluid “absorbs” water and uremic toxins from the system
- In CAPD (continuous ambulatory peritoneal dialysis), the patient usually
makes four regular exchanges within 24 hours
- In APD (automated peritoneal dialysis), the patient is hooked up to the
machine every night for 4–6 fluid exchanges
Dialysis and drugs
• Both hemo- and peritoneal dialysis remove drugs
• Factors affecting the removal of drugs:
– Molecular weight (e.g. vancomycin and amphotericin large
– not removed)
– Plasma protein binding (if more than 90%, dialysability is
often poor)
– Volume of distribution (large with e.g. tricyclics - most of
the drug in tissues -> low elimination, rebound
phenomenon)
– Dialysis method and equipment (i.a., dialysis membranes)
– Dialysis conditions (duration, blood and dialysate flow
rate)
Dialysis and drugs
• Determination of dialysis clearance of a drug:
V
Venous
Dialysate
solution
QB
blood flow
through the
dialyzer (QB)
Arterial
A
Dialysate
collection
Dialysis and drugs
• The relative volume of the drug being removed can be
calculated with the clearance achieved by dialysis
• The need of any additional dose caused by dialysis can be
estimated/calculated using the elimination fraction
• Well dialysable drugs are usually administered to a
dialysis patient after a dialysis session
• If the drug is removed both through dialysis and
extrarenal elimination, an extra dose of the drug is
usually also administered, equivalent to the volume of
drug removed by dialysis
• Dialysis treatment may also alter extrarenal drug
metabolism (i.a., liver metabolism) by removing uremic
toxins (CYP3A4 activity ↑ 27%)
Nolin et al. J. Am. Soc. Nephrol. 2006
Renal toxicity of drugs
• Increases the risk of aggravation of already
impaired renal function
• Should be avoided in patients with chronic kidney disease
• Problem can often be avoided by choice of drug
• Close monitoring of renal function/drug concentration
when an alternative safer option is not available
• Aminoglycosides, anti-inflammatory drugs, cold, some
bisphosphonates, several immunosuppressives
• Can be listed in the
portal
Why the database?
• Renal failure changes the pharmacokinetics of many drugs,
which requires modification of the dose and closer-than-usual
monitoring of the patient
• Differences in safety between drugs
• Differences in the documentation of drug safety
Choosing the drug/dosage/treatment
strategy correctly improves safety
• There is lot of information, but it is not updated, nor is it readily
available – poor penetration into clinical work
• Making independent information available for the benefit of
doctors, dentist and pharmacists improves the accuracy and
safety of medication and ability of healthcare personnel to
advice their patients
• Effective drug therapy is not denied on wrong grounds
development process
– Standardised operating models for data search
– Sources
• Medical literature (Pubmed)
• Information published by the creator in Europe, Australia
and the United States
– Data coding using standardised methods
• Mode of administration, classification, standard phrases
– Scientific assessment / inspection by a nephrologist
• Mode of administration is taken into account:
– Systemic (per oral, i.v., i.m., s.c.)
– Topical (dermatological, eye drops/ointments,
vagitories, local anaesthetics)
• Different recommendations for modification of
the dose in different uses have been taken into
account
• Any effect of the drug inducing renal injury has
been assessed
classification – colour coding system
A
No need for modification of dose/dosage interval
C
The information is not available or the recommendation is
estimated based on the pharmacokinetic characteristics of
Alert threshold
the substance
Modification of the dose or dosage interval is needed
D
Use should be avoided
B
For categories B and C, a detailed numerical information on the
magnitude of dosage modification is provided whenever available.
Distribution of classifications
References (linked to Pubmed) - approximately 5,000 references
[1] Arancibia A, Drouguett MT, Fuentes G, González G, González C, Thambo S, Palombo G.
Pharmacokinetics of amoxicillin in subjects with normal and impaired renal function. Int J Clin
Pharmacol Ther Toxicol 1982 Oct;20(10):447-53(PubMed Id: 7141752)
[2] Horber FF, Frey FJ, Descoeudres C, Murray AT, Reubi FC. Differential effect of impaired renal function
on the kinetics of clavulanic acid and amoxicillin. Antimicrob Agents Chemother 1986
Apr;29(4):614-9(PubMed Id: 3707111)
[3] Humbert G, Spyker DA, Fillastre JP, Leroy A. Pharmacokinetics of amoxicillin: Dosage nomogram for
patients with impaired renal function. Antimicrob Agents Chemother 1979 Jan;15(1):2833(PubMed Id: 426503)
[4] Davies BE, Boon R, Horton R, Reubi FC, Descoeudres CE. Pharmacokinetics of amoxycillin and
clavulanic acid in haemodialysis patients following intravenous administration of Augmentin. Br J
Clin Pharmacol 1988 Oct;26(4):385-90(PubMed Id: 3190988)
[5] Lawson DH, Henderson AK, McGeachy RR. Amoxycillin: pharmacokinetic studies in normal subjects,
patients with pernicious anaemia and those with renal failure. Postgrad Med J 1974
Aug;50(586):500-3(PubMed Id: 4618910)
[6] Francke EL, Appel GB, Neu HC. Kinetics of intravenous amoxicillin in patients on long-term dialysis.
Clin Pharmacol Ther 1979 Jul;26(1):31-5(PubMed Id: 445959)
[7] Slaughter RL, Kohli R, Brass C. Effects of hemodialysis on the pharmacokinetics of
amoxicillin/clavulanic acid combination. Ther Drug Monit 1984;6(4):424-7(PubMed Id: 6393464)
• Information on the use of more than 1,400
drugs during renal failure as well as dosage
recommendations
• Includes special licence drugs
• Vitamins and key micronutrients
• Search functions should always function with
generic names and brand names of drugs
• Updated every 3 months
uses:
• Portal use
• Doctors, dentists, pharmacists
• All health care units
• Drug chart reviews
• Integration to electronic patient record
systems
• Doctors, dentists
• Automatic decision support